Dissertação
Ativação de caspase-1 durante a infecção por Plasmodium: avaliação dos componentes envolvidos e implicações na patogênese da Malária.
Fecha
2011-08-19Autor
Marco Antônio Ataíde Silva
Institución
Resumen
Malaria is a major cause of death worldwide infecting around half-billion people
annualy. Years of studies on malaria pathogenesis has funneled into consent:
malaria is a highly pro-inflammatory disease where clinical manifestations are
directly correlated with the induction of high levels of pro-inflammatory mediators.
Here we demonstrated a pre-formed ASC dimers and active caspase-1 in
monocytes from P.vivax infected patients. Furthermore was observed immediate
release of IL-1β by peripheral blood mononuclear cells stimulated with LPS.
Additionally we show a new feature of malaria pathogenesis with deleterious
consequences even for the non-lethal murine model, Plasmodium chabaudi. We
report that caspase 1 is persistently active in macrophages and dendritic cells
during acute murine malaria, being this phenomenon NLRP3 and NLRP12
inflammasome-dependent. Usually, P.chabaudi infection resolves at fourth week,
but challenging of acute infected mice with low doses of LPS resulted in alarming
levels of IL-1β and TNFα, culminating in septic shock-like sydrome and
ultimately death. Susceptibility of mice to low LPS doses was associated with a
high background of caspase 1 activation and release of IL-1β. We have shown
that MyD88, ASC, IFN-γ and TNFR1 signaling controls these events. Together,
our results show that the inflammasomes platform is fully assembled and ready
to generate high IL-1β levels if an inducer of pro-IL1β, such as TLR agonists, is
present during malaria infection.